Numerous monoclonal antibodies to antigens associated with gastronintestional malignancies have been reported. Some of the more widely used monoclonal antibodies include monoclonal antibodies 17-1A (see Herlyn, M. et al, Proc. Natl. Acad. Sci. 76:1438-1442 (1979)), 19-9 (see Koprowski, H. et al, Somat. Cell Genet. 5:957-972 (1979)), B72.3 (see Colcher, D. et al, Proc. Natl. Acad. Sci. USA 78:3199-3202 (1981)), DuPAN-2 (see Metzgar, R. S. et al, Cancer Res. 42:601-608 (1982)), and a variety of monoclonal antibodies directed against carcinoembryonic antigen (see Boyer, C. M. et al, Antibody, Immunoconjugates and Radiopharmaceuticals, New York, N.Y., Mary Ann Liebert, Inc., pp. 105-161 (1988) and Muraro, R. et al, Cancer Res. 45:5769-5780 (1985)). Moreover, other monoclonal antibodies to colon associated antigens have recently been reported (see Boyer, C. M. et al, Antibody, Immunoconjugates and Radiopharmaceuticals, New York, N.Y. Mary Ann Liebert, Inc., pp. 105-161 (1988); Schlom, J. et al, Important Advances in Oncology, Philadelphia, Pa., J. B. Lippincott Co., Vol. 1, pp. 170-192 (1984); Nocera, M. et al, J.N.C.I. 79:943-948 (1987); Hughes, N. R. et al, Cancer Res. 46:2164-2171 (1986); Podolsky, D. K. et al, J. Clin. Invest. 77:1263-1271 (1986); and Richman, P. I. et al, Int. J. Cancer 39:317-328 (1987)). Of the above monoclonal antibodies, only monoclonal antibody 17-1A is of the IgG.sub.2a isotype and also mediates antibody dependent cell mediated cytotoxicity. Monoclonal antibody 17-1A, however, has also shown reactivity to normal adult kidney, thyroid, and pancreas whereas monoclonal antibody D612 does not. Another monoclonal antibody, designated monoclonal antibody CAA, has shown reactivity to both normal and malignant colonic epithelium (see Muraro, R. et al, Cancer Res. 39:39-44 (1987)). The molecular weight of the monoclonal antibody CAA-reactive antigen was shown to be &gt;200 kd and its expression correlated with the degree of cellular differentiation of colon carcinomas. The molecular weight of the reactive antigen and the pattern of reactivity to colorectal carcinomas versus normal tissues clearly distinguishes D612 from the monoclonal antibodies described above.
Several large molecular weight antigens associated with normal large intestinal epithelium have been previously described based on detection with polyclonal antibodies. The organ specific CMA (see Gold, D. V., Cancer Res. 41:767-772 (1981)) differs from the D612-reactive antigen in two major properties. Unlike D612, expression of CMA in colonic carcinomas is directly related to their differentiation. Moreover, unlike D612, CMA is predominantly located in the normal goblet cell vacuole while in carcinomas, it appears as cytoplasmic droplets; the intestinal M3 antigen (see Bara J. et al, Br. J. Cancer 41:201-221 (1980)) is very similar in its localization pattern to that of CMA, suggesting that these antigens may be related to one another. The large intestine mucin antigen (see DeBoer, W. G. R. M. et al, Path. 13:547-555 (1981)) differs from the D612-reactive antigen since it is associated with the goblet cell vacuole and D612 is not. Polyclonal antibodies have identified two other colon-associated antigens: the thermolabile CSAp (see Pant, K. D. et al, Immunol. Comm. 6:411-421 (1977)) and the thermostabile CSA (see Goldenberg, D. M. et al, Cancer Res. 36:3455-3463 (1976)), both of which are not absolutely restricted to the normal colon, since they can also be found at higher levels of the intestinal tract. CSAp is secreted and thus differs from the D612-reactive antigen in this property (see Pant, K. D. et al, Cancer 50:919-926 (1982)). Recently, monoclonal antibodies reactive with normal and neoplastic colonic mucosa have been reported. The cellular localization of the antigen detected by the GNM monoclonal antibody (see Hughes, N. R. et al, Cancer Res. 46:2164-2171 (1986)), mainly associated with mucin vacuoles, distinguishes it from the D612-reactive antigen. Two other groups have described several monoclonal antibodies against colonic epithelium based on their distinctive cellular staining patterns. Of 23 antibodies described by Podolsky, D. K. et al, J. Clin. Invest. 77:1263-1271 (1986), none showed the same staining characteristics of normal bowel as that of D612. Richman, P. I. et al, Int. J. Cancer 39:317-328 (1987) made an extensive evaluation of the normal and neoplastic tissue staining properties of 12 monoclonal antibodies. Of these, the PR.1A3 antibody had a similar but clearly distinct reactivity from that of D612; unlike D612, PR.1A3 exclusively stained the columnar absorptive cell and stained gastric surface eptithelium.
Each of the anti-colon carcinoma monoclonal antibodies described above has potential uses in the study of malignant and normal colon cell populations, and each has potential advantages and limitations in potential clinical applications. Some limitations include: (a) reactivity to a range of normal tissues in addition to colon carcinomas, (b) reactivity to other carcinomas or other malignancies, (c) reactive antigen being shed in the serum of cancer and/or normal patients (for applications other than serum assays), and (d) inadequate reactivity due to heterogeneity of carcinomas cell populations within a given tumor mass, among different masses within the same patient, and among masses from different patients.
The pattern of membrane associated staining, the molecular weight of the reactive antigen in Western blotting, the cell surface antigen expression, and the immunohistochemical studies demonstrating strong reactivity with malignant and normal gastrointestinal tissue and not to any other malignant or normal adult tissue, differentiates monoclonal antibody D612 from other monoclonal antibodies thus far described, and make it more desirable for several clinical applications in the management of human gastrointestinal malignancies.